The mathematical analysis of plasma HIV-1 viral load decay after the initiation of antiretroviral therapy has led to a number of important insights about the dynamics of HIV-1 infection, but not to a cure. Modeling, coupled to analysis of clinical data, suggested that with 100% effective therapy HIV could be eliminated from both short- and long-lived productively infected cell populations. Here, we propose to examine a set of problems related to the hurdles that have been encountered to eradicating HIV and thee development of effective HIV vaccines. We will pursue these ends by a combination of modeling and collaboration with experimental groups. In particular, we plan to continue to develop new viral dynamic models and use them to analyze both animal and patient data. Current HIV/SIV models have done a very poor job of realistically describing, the host immune response. Building on previous work, we plan to develop models that incorporate both cytolytic and noncytolytic CD8 responses to HIV. With vaccine trial data, we will look at the effects of elevated levels of antigen specific CD8 cells on the subsequent dynamics of viral growth upon SHIV/SIV challenge. We will model the effects of challenge dose and examine the reason why low-dose challenge frequently does not lead to infection. Natural antibody or other innate mechanisms may be at play here, and we will incorporate antibody responses into primary infection models. Other areas also will be explored such as Infection of gut associated lymphoid tissue, the possibility of cells being multiply infected, and issues of the stability of the latent reservoir.